Concerted actions of the ovarian steroid hormones estrogen (E) and progesterone (P), acting via their cognate receptors in uterine epithelial and stromal compartments, determine the maternal competency for embryo implantation. A clear understanding of the molecular pathways via which these hormone receptors regulate uterine functions during the reproductive cycle and pregnancy would require a definition of their cell type-specific roles in the uterus. Until recently, it was thought that estrogen receptor alpha (ER? present in the epithelial cells drives the E-induced proliferation of these cells during the reproductive cycle. Generation of a conditional knockout of ER? in uterine epithelium has revealed the surprising fact that E-induced proliferation of uterine epithelial cells is independen of the epithelial ER?. This finding has led to the hypothesis that E may act via the stromal ER? to control uterine epithelial proliferation by paracrine mechanisms. To test this new paradigm, it is necessary to create a conditional knockout mouse model in which ER? is deleted specifically in the uterine stromal cells. A major objective of this R21 application is to develop the Hand2-Cre transgenic mice in which Cre recombinase expression, under the control of an 11-kb regulatory region of the Hand2 gene, will be induced exclusively in the uterine stromal cells in response to P, thereby ablating the floxed ER? gene in these cells. This mouse model will provide novel insights into the role of ER? in directing stromal-epithelial dialogue during the establishment of pregnancy and would serve as an extremely valuable tool for researchers in the field of uterine biology.